Medrogestone (6,17.alpha.-dimethylpregna-4,6-diene-3,20-dione) is a known progestogen useful in hormone replacement therapy for inducing and reestablishing normal menstrual cycles (irregular cycles, secondary amenorrhea, oligoamenorrhea, etc.), assuring regular endometrial shedding and in arresting and controlling dysfunctional uterine bleeding (menhorrhagia, metrorrhagia, etc.). Medrogestone has been used alone and in conjunction with sequential estrogen treatment.
Medrogestone (6,17.alpha.-dimethylpregna-4,6-diene-3,20-dione) is conventionally prepared by the Grignard reaction of methyl magnesium bromide with 3.beta.-acetoxy-5.alpha.-hydroxy-17.alpha.-methyl-17.beta.-carbomethoxyand rostan-6-one to obtain 3.beta.,5.alpha.,6.beta.-trihydroxy-6.alpha.,17.alpha.-dimethyl-17.beta.-c arbomethoxyandrostane. Upon further reaction with methyl magnesium bromide, the corresponding pregnan-20-one is obtained. The, thusly, produced pregnan-20-one is oxidized with 8N chromic acid to yield 5.alpha.,6.beta.-dihydroxy-6.alpha.,17.alpha.-dimethylpregnan-3,20-dione which is converted into medrogestone by acid catalyzed dehydration (U.S. Pat. No. 3,170,936 Examples 3-6). This process leads to the production of three impurities which amount to about five percent of the product. These impurities can be removed from medrogestone with some difficulty and at considerable additional expense. Hence, avoidance of the production of these byproducts during the production of medrogestone would provide a markedly improved method for the manufacture of this valuable medicinal compound.
It is currently believed that the three major contaminants formed during the preparation of medrogestone are: (1) 6,17.alpha.-dimethyl- 17.beta.-isopropenylandrosta-4,6-dien-3-one (generated by methylation of the 17.beta.-methoxycarbonyl group to give the 17.beta.-1-hydroxy-1-methylethyl substituent which is dehydrated along with the 5.alpha.- and 6.beta.-hydroxyl groups by the conventional acid catalyzed process used in the final step of production); (2) 6-methylene-17.alpha.-methylpregn-4-ene-3,20-dione and (3) 6,17.alpha.-dimethylpregna-6,8(14)-diene-3,20-dione, each of which are formed as rearrangement products of the acid catalyzed dehydration of the 5.alpha.,6.beta.-dihydroxy intermediate.